A
study involving a gene implicated in AIDS has yielded a puzzling result:
A single nucleotide polymorphism, or SNP, was associated with an increased
risk for HIV infection and a delayed progression toward AIDS following
infection.

Researchers have identified five or six SNPs that may influence
susceptibility to HIV disease.

The SNP occurs in the regulatory region of the RANTES gene. RANTES (Regulated
upon Activation, Normal T-cell Expressed and Secreted) belongs to a class
of molecules known as beta-chemokines. The SNP increases the expression
of the RANTES gene, which produces molecules that are also called RANTES.
These molecules bind to the same targets used by the HIV virus to enter
cells. Thus, the competition for targets impedes the spread of the virus.

"By blocking the access of HIV to the binding sites, RANTES can act like
a chemical condom," says Philip M. Murphy, of the US National Institute
of Allergy and Infectious Diseases (NIAID). Murphy's group collaborated
on the study with investigators at the University of Manchester Medical
School, in the United Kingdom.

Individuals with the HIV virus progress from initial infection to onset
of AIDS at very different rates, and researchers have been trying to identify
genetic factors that protect against or increase susceptibility to disease.
The new findings support the hypothesis that a person's genome plays a
role in HIV disease, just as it does in other diseases.

Last year, another team of researchers reported an association between
the SNP and delayed progression of HIV disease in a population of infected
hemophiliacs. In the current study, individuals with the SNP who became
infected with HIV took about 40 percent longer to develop AIDS than did
those without the SNP. The mode of viral transmission for most of the
subjects was sexual contact. The researchers investigated variants of
the RANTES gene in HIV-positive and HIV-resistant individuals who participate
in the Multicenter AIDS Cohort Study.

The researchers have a plausible explanation for the delayed disease
progression. They already suspected that RANTES is a kind of endogenous
HIV suppressor, and having more RANTES is consistent with a slowing of
disease progression. But this does not explain why the SNP might the increase
risk for infection.

"We don't really understand the mechanism behind the increased risk for
infection," says Murphy, a senior investigator in the Laboratory of Host
Defenses at NIAID. "We've associated a SNP with a particular outcome,
and the reasons are plausible but speculative."

The 1999 RANTES study involving HIV-infected hemophiliacs in Japan did
not address the question of risk for infection. Nonetheless, the new findings
do fit a pattern. Since the mid-1990s, AIDS researchers have identified
five or six SNPs that may increase or decrease susceptibility to HIV disease.
The strength of the associations varies depending on the SNP, but several
studies have linked a mutation in a gene called CCR5 to better disease
outcomes.

"When you put all of these dots on a canvas," says Murphy, "you get a
picture of how people with different genetic backgrounds could get very
different disease outcomes over the course of 20 years."

AIDS researchers emphasize that no genetic factors are known to protect
against infection, so measures to prevent transmission of the virus are
as important as ever. The association studies have no immediate implications
for infected individuals. The hope is that understanding disease susceptibility
and responsiveness to drugs will facilitate more personalized treatments
down the road.